Kitchen Chemistry

Solomon first discovered the wonders of science before he started school, while visiting relatives in New York City. The trip included eye-opening visits to several museums, as well as the Hayden Planetarium, which Solomon remembers with particular fondness. After his return home to North Miami Beach, FL, Solomon began acquiring his science “toys”: a telescope, a microscope, a mineral collection, a Tasco bio-slide kit, and a Gilbert chemistry set. “I sort of took off on that,” he says, “and I guess I didn’t look back.” Over the years, the chemistry set expanded to a full chemistry laboratory in the garage, displacing the Solomons’ family car.

When Solomon was not conducting homemade chemistry experiments or occasionally getting stitches from breaking glass test tubes, he excelled at science in school, winning numerous science fairs. In his junior year of high school, he became involved in a program set up by Dade County in Florida, which allowed exceptional students to work with university professors. Solomon studied with a professor at the University of Miami (Miami, FL), using biochemistry and chromatography to study indols. The project led to Solomon becoming Florida’s first-ever finalist for the Westinghouse (now Intel) Science Talent Search in 1964.

When it came time to think about college, Solomon recalls that one of his friends from New York had frequently mentioned that Rensselaer Polytechnic Institute (RPI; Troy, NY) would be a great fit for Solomon’s interests. “I just connected with it, and that’s where I went. Although once I got there, I was shocked because I had never seen snow before, and it was pretty cold,” he says. Although adjusting to the weather took some time, what gave Solomon trouble in his first few years was organic chemistry, so much so that he considered switching majors to psychology, which, between some elective courses and his previous studies on schizophrenia, he found interesting. “But you know, I was really a chemist at heart,” he says, “and once I went into the physical chemistry courses, particularly quantum chemistry, it just took off.”

Solomon remembers two professors, Sam Wait and Henry Hollinger, who were influential in giving Solomon his first work in theoretical chemistry. “As an undergraduate, I became really interested in some concepts in transition metal inorganic chemistry,” says Solomon, “such as 10Dq, which is a splitting of d orbitals in a ligand field, and the Jahn–Teller effect, which is how electronic structure leads to geometry.” After graduating from RPI in 1968, those interests led Solomon to pursue doctoral studies with Don McClure, a spectroscopist and expert on transition metal systems who had recently moved to Princeton University (Princeton, NJ). “What I really liked about McClure is that he was really at the edge of theory with experiment[s]. … I could do some very fundamental experiments and evaluate how well the concepts worked,” says Solomon.

Unfortunately, Solomon soon found that theory and practice do not always see eye to eye. “I was taking a single crystal of rubidium manganese fluoride, which I had spent a long time getting perfectly set up, and putting it in a large piston in the middle of liquid helium, so I could see how the spectral states would be impacted by a distortion in the environment,” he explains. What he observed, however, was that the more data he put into his experimental model, the less the theory predicted the results. “And that got me really stressed out,” he says, “but Princeton was a wonderful place, where you could walk around campus and think about things and just keep thinking.” So, like Albert Einstein, John Nash, and others before, Solomon wandered the ivied grounds of Princeton’s campus until he figured out the problem. “There was a way that the analysis should have been done, in how you input the terms in a Hamiltonian and do the calculation, that people weren’t doing,” he says. A Hamiltonian is a mathematical function that can be used to generate the equations of motion of a dynamic system. When he went back to his computer and tried his new approach, the output looked just like his data and predicted several other things he had seen in the experiment as well (3). “And that was a big thing for me, in terms of feeling that I was a Ph.D. type and could really go on and solve whatever I wanted to work on,” he says.

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Solomon speaking to his laboratory group.

Small Molecules to Big Proteins

Shortly after Solomon received his Ph.D. in chemistry in 1972, his advisor McClure went on sabbatical and asked Solomon to stay and help oversee his research group. “I had started to think about being a professor, so it was a chance to see what running a lab was like,” Solomon says. He also had an idea of the research he would like to pursue once he became a professor, thanks to a symposium hosted by McClure and fellow Princeton chemist Tom Spiro. “They had brought in everybody from the broad field of physical inorganic chemistry, from the theoretical physicists to synthetic chemists,” Solomon says, “and I could really see the direction I wanted to go next, which was to look at really interesting molecules, such as metalloenzymes. All of a sudden you have these metal sites in proteins that have completely different spectroscopic features than anything seen in small-molecule inorganic chemistry.”

A leader in metalloenzyme research was Harry Gray at the California Institute of Technology (CalTech; Pasadena, CA), and Solomon wanted to set up a postdoctoral position there. First, however, Solomon spent a year in Copenhagen, Denmark to work under Carl Ballhausen, to better understand both sides of the theory/experiment coin. “McClure was an experimentalist who was at the edge of theory,” explains Solomon, “while Ballhausen was a theoretician who really focused on understanding data.” Together with Ballhausen, Solomon solved how some unusual potential energy surfaces contributed to the strange spectral shape of hex-aqua nickel (4). This research served as a natural segue for Solomon’s work at CalTech starting in 1974. When Gray first showed him a spectrum of the nickel ion in the enzyme carboxypeptidase, Solomon saw similar patterns to what he observed in hex-aqua nickel. He realized he could apply some of the same concepts he had learned for inorganic spectroscopy toward these proteins.

Solomon began studying blue copper proteins, such as plastocyanin and azurin, and based on several experiments, he determined the basic structure of the copper active site (5). These results were confirmed a few years later when Hans Freeman at the University of Sydney (Sydney, Australia) solved the crystal structure of a blue copper protein (6). Solomon continued to study blue copper proteins when he moved back to the East Coast in 1975 to join the Massachusetts Institute of Technology (MIT; Boston, MA) as an assistant professor.

At MIT, he began looking at the spectroscopic features of binuclear copper proteins that bind oxygen. He also expanded his work to two other areas: (i) examining the excited states of photoactive transition metal complexes to understand inorganic photochemistry and (ii) investigating how small molecules on metal oxide surfaces are activated for catalysis. By 1982, however, when he joined Stanford University as a professor, he enjoyed working on biological metals so much that it became the dominant focus of his laboratory.

Non-Heme in Northern California

Solomon’s exposure to a wide variety of spectroscopic techniques at CalTech and MIT, such as novel types of magnetic circular dichroism and x-ray photoelectron spectroscopy specially designed for protein analysis, established his ability to utilize different experimental methods as well as develop new ones. This ability became an important component of Solomon’s own laboratory and played a major role in his decision to move from MIT to Stanford. “I wanted to have a wide range of methods available that we could apply rigorously to study metalloenzymes and related systems,” he says, “and having the synchrotron [at Stanford] was attractive and gave me a chance to put together a really unique spectroscopy laboratory.” Of course, other factors, such as the balmy California weather, also helped him make his decision to move to Stanford. “I spent some time out in Stanford in January when I got invited to join. I’d left a snowstorm in Boston and ended up eating at an outdoor Mexican café. That was pretty different,” he says.

After he arrived at Stanford, Solomon became interested in proteins containing non-heme iron, which posed an experimental difficulty. Most researchers believed non-heme iron was too difficult to study because it had no spectroscopic features. “Heme has these porphyrin rings,” explains Solomon, “and your blood has very intense absorption because of this porphyrin. Non-heme sites don’t have it, so how do you see them?” Solomon adds that non-heme irons are ferrous, and thus have an even electron spin, meaning that electron-spin resonance techniques also would not work to study them. However, because these atoms are intense in the magnetic circular dichroism (MCD) spectrum, Solomon developed a variable-temperature variable-field (VTVH) MCD method to study these ions (7)

Over the years, VTVH MCD has provided insight into the geometric and electronic structures of many non-heme ferrous enzymes. For Solomon, the most exciting benefits of developing this new method were that he could now team up with other researchers and work on many interesting applications. “I really love to collaborate with key researchers who are studying different enzymes and mutants related to a disease state or such. It’s great when we can evolve our research to deal directly with health issues.” For instance, Solomon’s studies have helped mechanistically define how certain phenylketonuria (PKU) mutants affect catalysis (8). He has also worked with the anticancer drug bleomycin, a fairly large iron-containing peptide antibiotic that behaves as a pseudoenzyme and can break double-stranded DNA, showing how this compound activates oxygen and subsequently cleaves DNA (9).

In his PNAS Inaugural Article (1), Solomon collaborates with Graham Moran and Jonathan Spencer to work on another pair of intriguing non-heme iron enzymes. “There are two broad classes of reactions that these enzymes do. One class of enzymes does H-atom abstraction, and the other class does an electrophilic attack on double bonds. Now the question is, ‘how do they relate to each other?”’ says Solomon. As luck would have it, both Moran and Spencer worked on enzymes that used the same substrate, but each with a different chemistry. Using multiple spectroscopic methods, Solomon shows that both of these enzymes go through the same intermediate, “and we can see how that intermediate should be very effective at both types of reactions,” he says. The study shows that the difference between the classes is how the protein orients the substrate.

In the future, Solomon would like to explore how the other oxygen-activating systems, such as those using copper or molybdenum, relate to iron activators and to each other in their reaction centers. He is also interested in studying how metal ions in proteins interact with their highly organic environment. To that end, Solomon has teamed up with Keith Hodgson and Brett Hedman at the Stanford Synchrotron Radiation Laboratory to design new x-ray spectroscopic methods that can assess the covalency of bonds and orbitals (10). Solomon plans to apply this technique to heme to study the delocalization of iron in the porphyrin ring. So far, at least, Solomon has not found a scientific question for which he could not design a method, but if he should ever get stumped, he can always head back to Princeton’s grounds for inspiration.